1. Field of the Invention
This invention relates to use of Chaperonin 10 for modulating Toll-like receptor signaling and/or Toll-like receptor inducible immunomodulator production and/or secretion. More particularly, this invention relates to modulation of Toll-like receptor inducible cytokine and chemokine secretion for treatment of diseases, disorders and conditions resulting from excessive immunomodulator secretion. This invention also relates to producing, designing and/or screening agonists and antagonists of Chaperonin 10.
2. Description of the Related Art
The Toll-like receptor family plays an important role in inflammation and immunity in insects, animals and plants. Toll-like receptors (TLRs) are expressed by cells of the mononuclear lineage including lymphocytes, macrophages and dendritic cells.
TLR2 is activated by TLR2 agonists such as lipoteichoic acid and lipopeptides, which can be components of the outer wall of certain bacteria. TLR3 is activated by agonists such as double stranded RNA derived from viruses.
TLR4 is activated by lipoproteins or lipopolysaccharide (LPS) or endotoxin, which is a component of the outer wall of gram-negative bacteria.
TLR activation by pathogens, or by molecules derived therefrom, induces intracellular signaling that primarily results in activation of the transcription factor NF-κB (Beg, 2002, Trends Immunol. 2002 23 509-12) and modulation of cytokine production. However, a series of other pathways can also be triggered, including p38 mitogen activated kinase, c-Jun-N-terminal kinase and extracellular signal related kinase pathways (Flohe, et al., 2003, J Immunol, 170 2340-2348; Triantafilou & Triantafilou, 2002, Trends Immunol, 23 301-304). The patterns of gene expression induced by ligation of the different TLRs are distinct but often overlap. For instance a large proportion of the genes upregulated by TLR3 agonists and double stranded RNA are also upregulated by TLR4 agonists and LPS (Doyle et al., 2002, Immunity, 17 251-263). TLR4 activation by LPS in macrophages results in TNF-α, IL-12, IL-1β, RANTES and MIP1β secretion (Flohe et al., supra; Jones et al., 2002, J Leukoc Biol, 69 1036-1044).
Mammalian chaperonin 10 (also known as heat shock protein 10) was first described as a mitochondrial protein involved in protein folding, and is a homologue of the bacterial protein GroES. GroES and chaperonin 10 (Cpn10) oligomerise into seven member rings that bind as a lid onto a cup-like structure that comprises seven GroEL or Hsp60 molecules, which tether denatured proteins to the complex (Bukau & Horwich, 1998, Cell, 92 351-366; Hartl & Hayer-Hartl, 2002, Science, 295 1852-1858). Cpn10 is also frequently found at the cell surface (Belles et al., 1999, Infect Immun, 67 4191-4200; Feng et al., 2001, Blood, 97 3505-3512) and in the extracellular fluid (Michael et al., 2003, J Biol Chem, 278 7607-7616; Johnson et al., 2003, Cir Rev Immunol, 23 15-44).
Cpn10 has also been shown to be a suppressive factor present early in pregnancy and has shown immunosuppressive activity in experimental autoimmune encephalomyelitis, delayed type hypersensitivity and allograft rejection models (Zhang et al., 2003, J Neurol Sci, 212 37-46; Morton et al., 2000, Immunol Cell Biol, 78 603-607).
A recent study using Mycobacterium tuberculosis Cpn10 described in International Publication WO 02/40038, suggests that this molecule may have efficacy in treating disorders such as cancer, allergic reactions and/or conditions mediated by Th2-type immune responses. It is proposed that this may be achieved through induction of cytokines such as TNF-α and IL-6.
However, the mechanism of action by which Cpn10, and in particular mammalian Cpn10, exerts its immunoregulatory effects has remained obscure.